PROJECT SUMMARY/ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction and dyspnea and is the fourth leading cause of death in the United States. COPD is accelerated in HIV even in the current era of antiretroviral therapy (ART). Because standard COPD treatments have not been developed for or tested in HIV, they may lack efficacy or have significant side effects. Understanding how COPD develops in HIV is important in identifying novel targets for disease prevention and treatment. We have shown that distinct, but often overlapping phenotypes of COPD exist in HIV and are critical in understanding COPD pathogenesis and in personalizing treatment. Our work indicates that >70% of HIV+ outpatients manifest at least one COPD phenotype. These phenotypes are associated with a greater burden of respiratory symptoms and with mortality independent of smoking and CD4 cell count. Goals of this proposal are to utilize our existing longitudinal cohort, bio-specimens, and imaging bank to address scientific gaps in understanding of phenotypes and pathogenesis of HIV pulmonary disease and to extend follow-up of our HIV+ cohort up to 10 years. The overall hypotheses of this proposal are that discrete phenotypes of HIV COPD differ in their trajectories, biomarkers, and risk factors and that co-infections including persistent viral infection or microbial translocation are linked t HIV COPD. Results will be the longest study of lung function to date in the era of ART and will allow us to develop better markers of disease risk, identify mechanistic pathways, and target high-risk individuals for future interventions. We will test our hypotheses with the following aims Aim 1. To test the hypothesis that HIV COPD phenotypes have diverse disease trajectories and variable response to ART. Aim 2. To test the hypothesis that HIV COPD phenotypes have unique biomarkers and that specific biomarkers identify at-risk individuals. Aim 3. To test the hypothesis that chronic antigenic stimulation from HIV persistence, viral co-infections, or microbial translocation is linked to abnormal lung function. This research proposal specifically addresses several critical knowledge gaps in HIV COPD, an important cause of non-AIDS morbidity and mortality. Given that changes in COPD are seen over many years, it is necessary that longitudinal, well-characterized cohorts are used to evaluate these important and evolving complications. We will utilize our established, multicenter cohort to determine the course of HIV COPD phenotypes over 10 years and answer several key questions about HIV COPD including the effect of ART initiation, the utility of peripheral biomarkers, and the role of residual HIV an other sources of chronic antigenic stimulation in lung dysfunction. This innovative proposal will leverage existing resources and is highly likely to advance understanding of HIV lung disease, identify novel biomarkers and targets for therapy, and fill gaps in knowledge about the role of chronic infections in HIV-associated COPD, an objective directly responsive to RFA-14-023.